PAUL T. FINGER, MD

We have all seen successful radiotherapy for choroidal melanoma or orbital tumors marred by sight-limiting complications. While radiation cataracts can be repaired, radiation maculopathy and optic neuropathy continue to be the most common causes of severe, irreversible vision loss.1-5

Retinal complications related to radiation treatment have been reported since the 1930s.1,2 Ionizing radiation, particularly when used to treat retinoblastoma3 and choroidal melanoma,4 has been reported as a cause of radiation retinopathy (an exudative and vaso-occlusive complication similar to diabetic retinopathy). Furthermore, optic neuropathy is a relatively uncommon complication of radiation therapy characterized by dam age to the optic nerve that is typically sustained as a re sult of therapy for tumors of the choroid, retina, orbit or sinuses.5-8

Treatment of retinal complications of radiation therapies has been limited. While laser photocoagulation for retinal vascular damage has been some what successful,9 radiation maculopathy typically causes perma nent vision loss.3-5 Radiation-induced optic neuro pathy has a similarly bleak prog nosis.6-8 However, four studies have confirmed that treat ment with anti-VEGF agents may provide benefit in patients with radiation-induced vasculopathy.10-17 This article summa rizes our experience at the New York Eye Cancer Center.

BEVACIZUMAB FOR RON

Radiation optic neuropathy (RON) can be subclassified into early and late onset. Early RON occurs within several weeks or months of radiation therapy. Late RON occurs years later. Further, RON can affect the anterior portion of the optic nerve or its posterior extent (orbital, retro-orbital). While anterior RON tends to be associated with ophthalmic plaque and proton-beam irradiation for choroidal melanoma, posterior RON appears more often after external-beam radiation therapy for orbital, sinus, and intracranial tumors. RON almost invariably ends with optic nerve atrophy and severe vision loss.4-8 Though past efforts at treatment have consisted of corticosteroids, anticoagulation agents, and hyperbaric oxygen therapy, none of these are widely used due to poor efficacy and cost-ineffectiveness.4-8

In 2007, I reported the first case of late anterior RON treated with bevacizumab (Avastin, Genentech).10 This 69-year-old woman had been successfully treated with palladium 103 plaque therapy (optic disc dose 132 Gy) for choroidal melanoma. Eighteen months after plaque, she developed a late anterior RON–associated decrease in visual acuity from 20/20 to 20/32. She also noted a subjective "central haze" in vision. Ophthalmoscopy showed optic disc neovascularization, edema, and hemorrhages (Figure 1). Seven days after her first injection of bevazicumab (1.25 mg/0.05 mL), ophthalmoscopy revealed slightly diminished edema and neovascularization with markedly reduced hemorrhage. However, the patient reported resolution of her "haze" and her visual acuity had returned to normal.

Figure 1. Effect of intravitreal bevacizumab on radiation optic neuropathy (RON). Top left: Pretreatment RON is seen as optic disc hemorrhage and edema. Top right: Color photo showing maintenance of regression of RON after three years of treatment. Bottom left: Pretreatment fluorescein angiogram in arteriole-venous phase, demonstrating optic disc edema. Bottom right: Marked regression of disc edema after three years of treatment.

During subsequent evaluations (and injections) at six and 12 weeks, the patient maintained 20/20 vision while the optic nerve edema decreased as the optic nerve cup reformed. She has been given multiple periodic bevacizumab injections at six- to 12-week intervals and is 20/20 now 39 months since her first injection (Figure 1). She is not alone: more than a dozen patients have been similarly treated at the New York Eye Cancer Center, and the majority have been stabilized or improved for more than two years. These results stand in stark contrast to the natural history of late anterior RON.

INITIAL REPORTS ON BEVACIZUMAB FOR RADIATION MACULOPATHY

It has been four years since we first treated radiation maculopathy with intravitreal bevacizumab.11,12 Most patients had been treated with palladium 103 plaque irradiation for choroidal melanoma. Currently, patients are given periodic injections (four-, eight- or 12-week intervals) of bevacizumab (1.25 mg/0.05 mL). Encouraged by early, and then persistent, reductions of macular edema, hemorrhages and exudates, we titrated the number of injections needed to stabilize them over time.

In our first report, all six patients experienced regression of macular edema and five experienced regression of retinal hemor rhages.11 The one patient without retinal hemorrhage regression stabilized but did not improve. Four of six patients were noted to have regression of cotton-wool spots, and the other two had no cotton-wools spots to begin with. Stabilization or regression of microaneurysms and neovascularization was noted.

Not one patient in this study lost visual acuity. Three had post-treatment visual acuities of 20/20, one presented and maintained 20/20 vision, and another was stable at 20/80. The sixth patient, whose visual acuity was 20/320, improved to 20/100. There were no cases of endophthalmitis, allergy, retinal detachment, or vitreous hemorrhage. Reports of transient "blue or black floating round objects" were attributed to air bubbles.

BEVACIZUMAB FOR RADIATION MACULOPATHY II

The next published study of bevacizumab for radiation re tinopathy was extended to 21 pa tients.12 Most had been treated with palladium 103 or iodine 125 plaque brachy therapy. A mean of 3.8 injections of bevacizumab (1.25 mg/0.05 mL) were given over a mean follow-up period of 7.8 months. Visual acuity improved or stabilized in 86% of patients. Three experienced gains in visual acuity of two or more lines. An equal number did not finish the study: one be cause of no improvement from an initial visual acuity of counting fingers, one because of a loss of visual acuity of one line, and one due to poor compliance.12

The most common findings in patients examined by ophthalmoscopy, fluorescein angiography, and fundus photography were decreased vascular transudation evidenced by diminished retinal edema and restoration of the retina on OCT. In general, there was considerable resolution of retinal hemorrhages and cotton-wool spots, as well as focal closure of intraretinal microangiopathy.12

Despite the larger cohort, there were no additional adverse events.

EARLY RESULTS OF RANIBIZUMAB FOR RADIATION MACULOPATHY

We most recently reported early findings of an openlabeled, Genentech-sponsored, phase 1 clinical trial on five patients treated with ranibizumab (Lucentis, Genentech) for radiation maculopathy.13 In this study, all patients had been treated with palladium 103 ophthalmic plaque radiation therapy to a foveal dose of 62 Gy. Intravitreous injections were given every month for four consecutive months and then at the discretion of the principal investigator.

As reported, at a mean follow-up of eight months, the mean number of injections for the five patients was 8.2.13 Four of the five patients treated experienced improvements in visual acuity, with a mean improvement of six ETDRS letters. Without the one patient whose visual acuity worsened (from 20/32 at baseline to 20/40-2, or a seven-letter loss), the four remaining patients experienced a mean improvement of 9.5 letters. One hundred percent of patients presenting with hemorrhage or hard exudates (or both) had regression of these findings. While all patients presented with macular edema, only one had complete regression of edema. The remaining four were found to have regression of persistent macular edema.

Another key measurement was change in central foveal thickness (Figure 2). OCT documented a mean decrease of 146 μm over the eight months of the study. All five patients experienced a reduction in central foveal thickness.13

Side effects included multiple injection-related transient increases in intraocular pressure, several subconjunctival hemorrhages, and one transient facial swelling that resolved in one week. No cardiopulmonary or systemic vascular events were noted.13

NUANCES AND PEARLS

That said, there are certain nuances that I would like to share with those physicians who will use intravitreal anti-VEGF therapy for radiation maculopathy and optic neuropathy.

First, when treating radiation maculopathy in an eye with an intraocular tumor, one must not only know which is the correct eye, but also the location of the tumor. One does not want to inject into or through the tumor into the vitreous. This may cause a vitreous hemorrhage or worse. Approaching the eye from the side opposite the tumor allows you to utilize the tumor-related scotoma to hide your approach to needle placement. Some patients find this less stressful.

Second, the macular radiation dose makes a difference.18 Intravitreal anti-VEGF treatment of tall or large tumors (associated with relatively large radiation doses to the fovea and optic nerve) is less likely to spare vision over time. This does not mean it should not be attempted. It has been my experience (in these cases) that some vision may be spared or vision extended.

Third, treatment of longstanding radiation maculopathy or optic neuropathy is less likely to work. Including these patients in the previously mentioned studies has diminished our results. Therefore, it is important to start therapy as soon as there is loss of vision, since vision loss is associated with objective findings of etiologic intraocular radiation vasculopathy and transudation. Patients treated for longstanding macular edema, fibrosis, or optic atrophy tend to have little or no recovery of vision.

DISCUSSION

With up to four years' experience using intravitreal anti-VEGF therapy for radiation maculopathy and optic neuropathy, I still prefer to first offer laser demarcation to suppress the ischemic drive likely causing elevated intraocular VEGF.19 Laser delivered in one or two sessions may avoid or delay the need for periodic intravitreal injections. However, in cases where laser does not work or when the tumor is beneath the fovea, anti-VEGF therapy offers the patient the best chance for vision preservation.

Though the four preceding trials are small, there exist additional case series with similar findings.10-17 All suggest that further research on the use of anti-VEGF agents in radiation-induced complications of the retina and macula are warranted. Intravitreal bevacizumab and ranibizumab have improved or stabilized vision in my patients that have developed RON and radiation maculopathy. RP

Paul T. Finger, MD, is clinical professor of ophthalmology at the New York University School of Medicine and director of the New York Eye Cancer Center. Dr. Finger reports no financial interest in any products mentioned in this article. Dr. Finger can be reached via e-mail at pfinger@eyecancer.com.